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Home , Amantadine, Remdesivir, Ribavirin, Rimantadine

Journal of Personalized Medicine

Communication Anti-Inflammatory Effects of and : Possible Therapeutics for the Treatment of Covid-19?

Félix Javier Jiménez-Jiménez 1,* , Hortensia Alonso-Navarro 1 , Elena García-Martín 2 and José A. G. Agúndez 2

1 Section of Neurology, Hospital Universitario del Sureste, Arganda del Rey, E-28500 Madrid, Spain; [email protected] 2 University Institute of Molecular Pathology , UNEx. ARADyAL Instituto de Salud Carlos III, E-10071 Cáceres, Spain; [email protected] (E.G.-M.); [email protected] (J.A.G.A.) * Correspondence: [email protected]; Tel.: +34-636968395

 Received: 2 October 2020; Accepted: 6 November 2020; Published: 9 November 2020 

Abstract: We have reviewed current data on the anti-inflammatory effects of amantadine and memantine in clinical and in vivo models of inflammation, and we propose that these effects have potential interest for the treatment of the SARS-CoV-2 (COVID-19 disease). To that end, we performed a literature search using the PubMed Database from 1966 up to October 31 2020, crossing the terms “amantadine” and “memantine” with “inflammation” and “anti-inflammatory”. Amantadine and/or memantine have shown anti-inflammatory effects in chronic C, in neuroinflammation induced by sepsis and by lipopolysaccharides, experimental models of , spinal cord injury, and respiratory diseases. Since the inflammatory response is one of the main pathogenetic mechanisms in the progression of the SARS-CoV-2 infection, anti-inflammatory effects of amantadine and memantine could be hypothetically useful in the treatment of this condition. This potential utility deserves further research.

Keywords: amantadine; memantine; anti-inflammatory effects; SARS-Cov-2; COVID-19; therapy

1. Introduction Amantadine (adamantan-1-) is an derivative which was used to treat influenza caused by influenza type A (the antiviral effects of amantadine are based on the ability to interfere with the viral M2 protein, therefore interfering with viral replication), although today it is not recommended for this indication because of the development of [1,2]. Amantadine is also useful for the treatment of Parkinson’s disease (PD) at early stages (it decreases symptoms of bradykinesia, rigidity, and ) and to treat levodopa-induced in this disease. The mechanisms of action of amantadine in PD include non-competitive antagonism of the N-methyl-D-aspartate (NMDA) receptor (NMDAR), an increase of release, a reduction of dopamine reuptake, and mild (by antagonism of the nicotinic receptor) and D2 receptor actions [1,3]. Amantadine is also widely used as an effective and safe drug in the treatment of in patients with multiple sclerosis [4] and has shown efficacy in persistent vegetative state due to severe [5] or to severe cerebral hemorrhage [6]. Memantine (3,5-dimethyladamantan-1-amine) is a non-competitive, low-affinity, voltage- dependent antagonist of NMDA receptors, and also acts as an antagonist of both the nicotinic cholinergic and serotonergic (5-HT) type 3 (5-HT3) receptors. Memantine is one of the two classes of drugs approved for clinical use in moderate to severe Alzheimer’s disease (AD) [7–9]. Other clinical uses

J. Pers. Med. 2020, 10, 217; doi:10.3390/jpm10040217 www.mdpi.com/journal/jpm J. Pers. Med. 2020, 10, 217 2 of 15 J. Pers. Med. 2020, 10, x FOR PEER REVIEW 2 of 13 includeuses include the treatment the treatment of vascular of vascular dementia, dementia, dementia dementia of Wernicke-Korsako of Wernicke-Korsakoffff syndrome, syndrome, and acquired and pendularacquired nystagmuspendular nystagmus of multiple of sclerosis multiple [sclerosis10]. [10]. TogetherTogether with with these these main main mechanisms mechanisms of action of action and clinical and clinical uses, both uses, amantadine both amantadine and memantine and havememantine shown importanthave shown anti-inflammatory important anti-inflammatory actions. Because actions. inflammatory Because inflammatory response with response the so-called with “cytokine-storm”the so-called “cytokine-storm” (triggering viral (triggering sepsis and viral inflammatory-induced sepsis and inflammatory-induced lung injury) lung is one injury) of the is mainone pathogeneticof the main mechanismspathogenetic inmechanisms the progression in the of prog theression SARS-CoV-2 of the (COVID-19) SARS-CoV-2 infection (COVID-19) [11], weinfection should speculate[11], we onshould the hypothesisspeculate on that the amantadine hypothesis andthat memantineamantadine could and memantine be useful as could adjunctive be useful therapy as foradjunctive the treatment therapy of for this the condition. treatment Forof this this condit purpose,ion. For we this undertook purpose, a we literature undertook search a literature using the PubMedsearch using database the PubMed from 1966 database up to 31 from October 1966 2020,up to crossing31 October the 2020, terms crossing “amantadine” the terms and “amantadine” “memantine” withand “inflammation”“memantine” with and “inflammation” “anti-inflammatory”. and “anti-inflammatory”. The whole search The retrieved whole asearch total ofretrieved 337 references, a total whichof 337 were references, examined which manually were examined one by manually one, before one the byreferences one, before strictly the references related strictly to this related issue were to selected.this issue The were flowchart selected. for The the flowchart selection for of the studies selection is represented of studies inis represented Figure1. in Figure 1.

Figure 1. Flowchart of the studies on anti-inflammatory effects of amantadine and memantine. For more information, visit www.prisma-statement.org. Figure 1. Flowchart of the studies on anti-inflammatory effects of amantadine and memantine. 2. Anti-Inflammatory Effects of Amantadine 2. Anti-Inflammatory Effects of Amantadine Amantadine and its derivative , in combination with α2b (IFNα2b) and Amantadine and its derivative rimantadine, in combination with interferon α2b (IFNα2b) and , have shown higher efficacy in the treatment of chronic in non-responders to ribavirin, have shown higher efficacy in the treatment of chronic hepatitis C in non-responders to

J. Pers. Med. 2020, 10, 217 3 of 15

IFNα2b than the combination of IFNα2b with ribavirin, measured as the end-of-treatment response (ETR), according to two literature reviews [12,13]. Amantadine combined with pegylated IFNα2b and ribavirin has also shown efficacy in the treatment of chronic hepatitis C (measured as a sustained virological response—SVR) [14,15], which was higher in drug-naïve than in non-responders to IFNα2b [16]. While several studies have shown the lack of effect of amantadine alone in the treatment of patients with chronic hepatitis C non-responders to IFNα2b, both in reducing viremia and in reducing aminotransferase (ALT) levels [17,18], other studies have shown a sustained reduction in ALT levels in patients treated with this drug, suggesting its potential anti-inflammatory activity [12,19]. Amantadine has shown the ability to reduce the induction of inflammatory factors such as RANTES (regulated on activation, normal T cell expressed and secreted; Chemokine (C-C motif) ligand 5) in a dose-dependent manner, and the activation of p38 MAP (mitogen-activated protein) kinase and c-Jun-NH2-terminal kinase (JNK) in cell cultures of bronchial epithelial cell lines infected with influenza virus (the reduction in the activation of p38 MAP kinase and JNK seems to be related to the inhibition of virus replication, because amantadine did not inhibit the activation of these kinases induced by tumour necrosis α -TNF-α)[20]. Both amantadine and memantine showed a positive effect on neurological deficits and in the improvement of rats with experimental allergic encephalomyelitis (EAE), an experimental model of multiple sclerosis, increasing both the number and activation of microglial cells, and decreasing mRNA expression of interleukin-6 (IL-6) and, to a lesser extent, expression of IL-1β, TNF-α mRNA, but did not affect the activation of astrocytes [21]. Amantadine injected intraperitoneally in mice reduces neuroinflammation by attenuation of the increase of IL-1β expression induced in a model of sepsis induced by caecal ligation and puncture [22]. Administration of amantadine to rats with spinal cord injury showed a protective effect related to endothelial development and angiogenesis, reduction in inflammation, and markers of apoptosis and oxidative stress [23]. Finally, amantadine inhibited the release of microglial pro-inflammatory factors and increased the expression of neurotrophic factors such as glial-derived neurotrophic factor (GDNF) from astroglia in rat midbrain mixed -glia cultures challenged with lipopolysaccharide (LPS) or the neurotoxin 1-methyl-phenyl-pyridinium ion (MPP+), these actions being independent of NMDA receptor inhibition [24].

3. Anti-Inflammatory Effects of Memantine Memantine has shown the ability to decrease neuroinflammation induced by intraventricular infusion of LPS in rats by reducing microglia activation [25]. Like amantadine, as previously stated, memantine improved EAE in rats [21]. Memantine has shown a potent protective effect against lesions induced by 6-hydroxydopamine (OHDA) in dopaminergic PC12 cells related to reversing nerve growth factor IB (Nurr77) upregulation [26]. Nurr77 activates the nuclear factor-κB (NF-κB) signalling pathway, potentiates the induction of pro-inflammatory expression, and enhances mouse resistance to LPS-induced sepsis by inhibiting NF-κB activity and suppressing aberrant cytokine production [26]. Memantine has shown anti-inflammatory effects on human microvascular endothelium induced by the pro-inflammatory cytokine TNF-α in an experimental in vitro blood-brain-barrier (BBB) model of human brain microvascular endothelial cells. Memantine prevents the attachment of monocyte THP-1 cells to human brain microvascular endothelial cells, preventing the increase in expression of cell adhesion molecules, such as intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), and E-selectin, and interfering with monocyte transmigration across the BBB model [27]. Memantine significantly decreased pulmonary inflammation induced by cigarette smoke combined with intratracheal injection of LPS in mice and in cultures of RAW264.7 cells through several mechanisms, J. Pers. Med. 2020, 10, 217 4 of 15 J. Pers. Med. 2020, 10, x FOR PEER REVIEW 4 of 13 severalwhich includedmechanisms, the attenuationwhich included of the the increased attenuatio releasen of the of increased cytokines release (TNF- ofα, cytokines IL-6, and (TNF- IFN-γα), and IL- 6,glutamate and IFN- inducedγ) and glutamate by cigarette induced smoke andby cigarette LPS; and smok the reductione and LPS; of NMDAand the receptorreduction 1 (NMDAR1,of NMDA receptorNR-1) and 1 (NMDAR1, the xCT subunit NR-1) and of the the x(c)(-) xCT subunit cystine of/glutamate the x(c)(-) antiporter cystine/glutamate (xCT, a cystineantiporter/glutamate (xCT, a cystine/glutamateexchanger) expression, exchanger) Ca2+ influx, expression, and phosphorylation Ca2+ influx, and of phosphorylation extracellular signal-regulated of extracellular kinase1 signal-/2 regulated(ERK1/2) [kinase1/228]. (ERK1/2) [28]. Memantine reverse prevented the increased expr expressionession of NMDAR1, NMDAR2B, Calpain, and Caspase 3 expression, and the decreased level of NMDAR2A, CaMKIIα, and cyclic AMP-response element-binding CREB CREB protein protein expression; expression; and and restored restored the the increased increased levels levels of of GFAP, GFAP, TNF-α, and iNOS, and and the the decreased decreased levels levels of of IL-10 IL-10 induced induced by by in intracerebroventriculartracerebroventricular injection injection of of streptozotocin streptozotocin (STZ) to rats [[29].29].

4. Amantadine, Amantadine, Memantine, Memantine, and COVID-19 First suggested suggested by by Tipton Tipton & & Wszolek Wszolek [30], [30 there], there are aremany many reasons reasons to think to think that these that these two non- two expensivenon-expensive drugs, drugs, amantadine amantadine and memantine, and memantine, could could be useful be useful in COVID-19 in COVID-19 therapy. therapy. Together with the previously mentioned antiviral effects effects on amantadine in , influenza, based on its ability to interfere with the viral M2 protein, recent reports suggest a possible antiviral action against SARS-CoV-2. Abreu et al. [31] [31] hypothesized a possible antiviral effect effect of amantadine by blocking a 5- α-helix channel (“ channel”) in a hydrophobic regionregion of the intramembraneintramembrane regionregion ofof COVID-19.COVID-19. Smieszek et al. [32] [32] showed that amantadine can down-regulate the expression of cathepsin L (CTSL) and other lysosomal enzymes, and these tw twoo mechanisms have been proposed as potentially useful in decreasing the ability of SARS-CoV-2 toto enterenter thethe cellscells andand toto decreasedecrease virusvirus replication.replication. This aside,aside, itit hashas been been shown shown that that memantine memantine is capableis capable of inhibiting of inhibiting the E the protein E protein of SARS-CoV-2, of SARS- CoV-2,which seems which to seems act as to an act ion as channel, an ion and channel, is related and to is viral related pathogenicity to viral pathogenicity [33]. All these [33]. reports All these focus reportson the possible focus on antiviral the possible effect antiviral of amantadine effect of and amantadine memantine and (Figure memantine2). (Figure 2).

Figure 2. MechanismsMechanisms involved involved in in the the antiviral antiviral effects effects of amantadine and memantine. However, clinical experience regarding the use of amantadine and memantine in the therapy of However, clinical experience regarding the use of amantadine and memantine in the therapy of COVID-19 is limited. In this respect, a recent preliminary report by Rejdak & Grieb [34] has shown COVID-19 is limited. In this respect, a recent preliminary report by Rejdak & Grieb [34] has shown that 10 patients diagnosed with multiple sclerosis and five PD patients, all of them under previous that 10 patients diagnosed with multiple sclerosis and five PD patients, all of them under previous treatment with amantadine, along with seven patients with cognitive impairment under previous treatment with amantadine, along with seven patients with cognitive impairment under previous treatment with memantine (these treatments had been used for at least three months previously treatment with memantine (these treatments had been used for at least three months previously to to enrolment in the study) with asymptomatic SARS-CoV-2 infection (all these individuals have enrolment in the study) with asymptomatic SARS-CoV-2 infection (all these individuals have been in contact with patients diagnosed with COVID-19 and showed positive real-time polymerase chain reaction—RT-PCR), remained asymptomatic after two-week quarantine, suggesting a potential

J. Pers. Med. 2020, 10, 217 5 of 15 been in contact with patients diagnosed with COVID-19 and showed positive real-time polymerase chain reaction—RT-PCR), remained asymptomatic after two-week quarantine, suggesting a potential preventive effect of amantadine and memantine against the development of symptomatic COVID-19. More recently, Aranda-Abreu et al. [35] reported an observational open-label study involving 15 patients infected with SARS-CoV-2 treated with 100 mg/day of amantadine for a period of 14 days. Diagnosis of SARS-CoV-2 infection was done by the presence of clinical symptoms compatible with COVID-19, and confirmation was done by positivity for IgG antibodies and negativity of IgM against SARS-CoV-2 at the end of the treatment. Together with amantadine, 14 patients received azithromycin 500 mg daily for 6 days, daily for 6 days, and celecoxib 200 mg daily for 6 days; three patients required ipratropium bromide/ 3 nebulisations per day during 5 days, and 2 oxygen mask 4 Lpm. All the patients recovered successfully.

5. Discussion, Conclusions, and Future Directions Konstantinidou & Papanastasiou [36] recently reviewed the most promising repurposed regimens for the therapy of COVID-19, which included antimalarial (chloroquine and ), cardioprotective (colchicines), angiotensin-converting enzyme 2 inhibitors, antiviral (, , ribavirine, lopinavir/), anti-inflammatory (tocilizumab, leronlimab, interferon λ) and antiparasitic drugs (, nitazoxanide) among others. More recently, Sarkar et al. [37] reported the current status and future perspectives of potential therapeutic options for COVID-19, including an important number of drug trials that are currently ongoing. These include antiviral drugs, antimalarial drugs, antibiotics and anti-parasitics, anti-inflammatory and immunosuppressive drugs, kinase inhibitors, monoclonal antibodies, hormonal preparations, and blood and blood-forming organs. According to this review, dexamethasone has been considered as a standard in the treatment of COVID-19, especially in severe cases, since a study conducted in the UK showed a 35% reduction in mortality rate in patients with mechanical ventilation and a 20% reduction in the mortality rate in patients who were given oxygen [38]. In contrast, a recent meta-analysis questioned the efficacy of corticosteroids in COVID-19, concluding that “with the use of corticosteroids, delayed recovery and a longer hospital stay were observed” [39]. Together with dexamethasone, remdesivir has been authorized and recommended for the therapy of COVID-19 in the US, where two studies have shown that this drug accelerated the patient’s recovery compared to , and reduced hospitalization period [37]. Finally, the antiviral Fapipavir has been recommended in China based on the results of two randomized trials [37]. Recombinant monoclonal antibodies, interferon-based therapies, convalescent plasma therapy, small-molecular drug therapies, and cell-based therapies are expected to show promising results while an effective vaccination is being developed. Despite that to date there are no effective and safe chloroquine or hydroxychloroquine dosage treatments for COVID-19, at least in the more severe (hospitalized) patients [36], and the fact that the combination of these drugs is no longer recommended in the US and by the World Health Organization, a recent retrospective open-label French study involving 1061 patients with confirmed COVID-19 (both symptomatic and asymptomatic, diagnosed through early unrestricted massive PCR screening) treated with the combination of hydroxychloroquine (200 mg three times daily for ten days) plus azithromycin (500 mg on day 1 followed by 250 mg daily for the next four days), has shown excellent results, with good clinical outcome and virological cure in 91.7%, prolonged viral carriage with final relativisation of PCR in 4.4%, and poor clinical outcome in 4.3%, with death in 0.75% of patients (all deaths due to respiratory failure) [40]. Moreover, a double-blind randomized trial to assess the efficacy and safety of hydroxychloroquine chemoprophylaxis in COVID-19 in healthcare personnel in a hospital setting is undergoing in Spain [41]. The possible usefulness of amantadine and memantine in the treatment of COVID-19 lies in two pharmacological effects: antiviral action and anti-inflammatory effects. The anti-inflammatory effects are summarized in the previous paragraphs, both in chronic hepatitis C and in neuroinflammation J. Pers. Med. 2020, 10, 217 6 of 15 induced by sepsis and by LPS, as well as experimental models of multiple sclerosis, spinal cord injury, and respiratory diseases. As we previously commented, two preliminary reports have suggested the clinical efficacy of amantadine and memantine in the treatment of COVID-19 [34,35]. This review has as its main limitation the fact that most of the studies published on the anti-inflammatory effects of amantadine and memantine (Tables1 and2) are related to chronic, rather than acute, models of neuroinflammation. Two studies were performed with experimental models of pulmonary disease, and other studies on chronic hepatitis C. Unfortunately, to our knowledge no studies have been published to date on cardiovascular inflammation (vascular inflammation being one of the main pathogenic factors), although the study by Wang et al. [27] reported anti-inflammatory effects of memantine in the human microvascular endothelium. In addition, clinical studies in humans with infection were open-label and/or included a low number of patients. Taking into consideration the previously mentioned limitations, in the light of available evidence, we suggest that the addition of amantadine or memantine as add-on therapy to other COVID-19 therapies could hypothetically improve the outcome. Therefore we propose the development of pilot double-blind studies evaluating the efficacy of amantadine and memantine as add-on therapy in the treatment of COVID-19. J. Pers. Med. 2020, 10, 217 7 of 15

Table 1. Studies assessing the anti-inflammatory effects of amantadine.

Authors, Year Country Model Study Design Main Findings [Ref] Open-label, single-arm study. 57 patients with initial viral response to IFNα2b but with the reappearance of low-level 34 patients (59.6%) showed sustained Gelderblom et al., HCV RNA at weeks 16 to 20. Initial induction therapy with The Netherlands Human hepatitis C virological response (SVR) and the other 23 2007 [14] amantadine, IFNα2b, and ribavirin during 6 weeks, and (40.4%) showed breakthrough or relapse. substitution of IFNα2b for pegylated IFNα2b later with a follow-up period of 24–48 weeks Randomized controlled trial involving 43 patients who did Significantly higher frequency of SVR in a not respond previously to the combination IFNα-2a plus group of 21 patients treated with pegylated Palabıyıko˘glu ribavirin for 48 weeks. Treatment with pegylated IFN-α2a Turkey Human hepatitis C IFN-α2a + ribavirin + amantadine than in et al., 2012 [15] (180 µg/kg /week) plus ribavirin (1000–1200 mg/day) and the other group of 22 patients treated with amantadine (200mg/day, 21 patients) or with amantadine amantadine alone. alone (200mg/day, 22 patients) for 48 weeks Multi-centre, open-label involving 168 patients (69 drug-naïve and 99 non-responders to previous therapy, 32 of them to IFN-α only and 67 to IFN-α plus ribavirin). Both Of the entire cohort, 35 (21%) discontinued groups started therapy with pegylated IFN-α2b (1.5 µg/kg early due to side effects or loss to follow-up. week), ribavirin (1000–1200 mg/day), and amantadine (200 SVR and end-of-treatment virological Younossi et al., United States of mg/day), for 4 weeks, followed by pegylated IFN-α2b (0.5 response (ETR) in 47.8% 34.3% and of Human hepatitis C 2005 [16] America µg/kg week ribavirin (1000–1200 mg/day), and amantadine patients of the drug-naïve group vs in (200 mg/day), for another 20 weeks. Patients with 28.6% and 19.4% for the group who had undetectable HCV RNA at week 24 continued this regimen previously failed to respond to a course of for a total of 48 weeks and were followed for another 24 treatment (p = 0.01). weeks. Patients with undetectable virus (<50 IU/mL) after 24 weeks of follow-up were considered to have SVR. Open-label study involving 18 patients with hepatitis C No significant reduction of serum alanine Parolin et al., Brazil Human hepatitis C non-responders to IFN-α. Treatment with amantadine 200 aminotransferase levels and of viral load 1999 [17] mg/day. between baseline and final values J. Pers. Med. 2020, 10, 217 8 of 15

Table 1. Cont.

Authors, Year Country Model Study Design Main Findings [Ref] Open pilot study involving 8 hepatitis C virus-positive Non-significant decrease in hepatitis C Kamar et al., renal-transplant patients with chronic active hepatitis and viremia, in aspartate aminotransferase France Human hepatitis C 2004 [18] increased alanine aminotransferase (ALT) levels. Treatment activity, and no changes in histology. with amantadine 200 mg/day. Follow-up of 6 months. Significant decrease in ALT activity Open-label prospective study involving 25 drug-naïve and 33 Reduction of ALT levels in 75% of patients Yagura & non-responders to IFN-α. Treatment with amantadine 100 at 4 months and 85% at 6 months after Japan Human hepatitis C Harada, 2001 [19] mg/day during 4 months and 200 mg/day during the therapy. HCV RNA levels did not modify subsequent 2 months. during the treatment period. Amantadine-induced inhibition of virus replication decreased p38 MAP kinase and Infection of bronchial epithelial cells in culture with influenza JNK activity and expression of RANTES in Asai et al., 2001 Bronchial epithelial cells virus and amantadine. Measurement of p38 MAP kinase and Japan infected cells. Amantadine did not inhibit [20] cultures JNK activation in the cells and RANTES concentrations in the p38 MAP kinase and JNK activation culture supernatants induced by tumour necrosis factor α (TNF-α). Amantadine and memantine suppressed Screening analysis of inflammatory mediators (cytokines and neurological symptoms of disease in EAE chemokines) in control rats, rats with untreated EAE, and rats and reduced expression of Female rats with experimental Sulkowski et al. groups rats of EAE treated with amantadine (100 mg/kg pro-inflammatory cytokines in the brain, Poland allergic encephalomyelitis 2013 [21] b.w./day), memantine (60 mg/kg b.w./day), LY 367385 (10 while antagonists of metabotropic (EAE) mg/kg b.w./day, an antagonist of mGluR1) or MPEP (10 mg/kg glutamate receptors (mGluR) did not affect b.w./day, an mGluR5 antagonist) the inflammatory process and the neurological symptoms of EAE rats. Measurements of learning and memory, and brain cortex expression of several mediators of inflammation in mice Amantadine attenuated CLP-induced Experimental model of controls (not being exposed to surgery or any drugs), mice neuroinflammation in the hippocampus United States of sepsis-induced cognitive Xing et al., 2018 treated with amantadine, CLP, or CLP plus amantadine 1 (the (i.e., interleukin (IL-1β and IL-6 levels) and America and dysfunction by caecal ligation [22] first dose of amantadine was given intraperitoneally 15 min dysfunction of learning and memory, but China and puncture (CLP) in male before the surgery to create CLP), and CLP plus amantadine 2 did not have significant effects on the mice (the first dose of amantadine was given intraperitoneally 6 h expression of toll-like receptors (TLRs) after the creation of CLP). J. Pers. Med. 2020, 10, 217 9 of 15

Table 1. Cont.

Authors, Year Country Model Study Design Main Findings [Ref] Spinal cord injury (SCI) induced by removing spinous processes and laminar arcs of T5–12 followed by laminectomy Amantadine had an inhibitory effect of T11-T12 and compression with a clip for 60 s at this level. Dogan & Karaka, Experimental spinal cord injury oxidative stress, inflammation, and Turkey Measurement of oxidative stress, inflammation, and 2020 [23] in male rats apoptosis, and ameliorated SCI effects by angiogenesis markers (histological examination of spinal cord inducing angiogenesis. sections) in control rats, rats with SCI, and rats with SCI treated with amantadine. Treatment of primary cultures with two dopaminergic Amantadine protected rat midbrain Primary cultures with different neurotoxins: lipopolysaccharides (LPS) and cultures from MPP+ and LPS toxicity by Finland and the composition of , 1-methyl-phenylpyridinim ion (MPP+). Measurement of inhibiting the release of microglial Ossola et al., 2011 United States of microglia, and astroglia production of tumour necrosis factor-alpha, Prostaglandin E2 pro-inflammatory factors, and increasing [24] America obtained from the (PGE2) release, (NO) production, glial-derived the expression of GDNF in astroglia, while mesencephalon of female rats neurotrophic factor (GDNF) gene expression, and changes in NMDA receptor inhibition was not related intracellular Ca2+. to the neuroprotective effect.

Table 2. Studies assessing the anti-inflammatory effects of memantine.

Authors, Year Country Model Study Design Main Findings [Ref] Amantadine and memantine suppressed Screening analysis of inflammatory mediators (cytokines and neurological symptoms of disease in EAE chemokines) in control rats, rats with untreated EAE, and rats and reduced expression of Female rats with experimental Sulkowski et al. groups rats of EAE treated with amantadine (100 mg/kg pro-inflammatory cytokines Poland allergic encephalomyelitis 2013 [21] b.w./day), memantine (60 mg/kg b.w./day), LY 367385 (10 in the brain, while antagonists of (EAE) mg/kg b.w./day, an antagonist of mGluR1) or MPEP (10 mg/kg metabotropic glutamate receptors (mGluR) b.w./day, an mGluR5 antagonist) did not affect the inflammatory process and the neurological symptoms of EAE rats. Memantine treatment attenuated Behavioural testing, histological examination, LPS-induced spatial learning and memory immunofluorescence studies, fluorescence in situ impairments, reduced the number of Neuroinflammation induced by hybridization and confocal microscopy in the dorsal activated microglia in the hippocampus Rosi et al. 2006 Italy chronic LPS infusion into the hippocampus in two groups: (LPS-infused; LPS-infused + without affecting resident microglia, and [25] 4th ventricle of rats memantine; and CSF-infused) and caged control groups returned Arc (activity-regulated (LPS-infused; LPS-infused + memantine; and artificial cytoskeletal associated protein) expressing CSF-infused) neuronal populations to control levels after LPS-infusion J. Pers. Med. 2020, 10, 217 10 of 15

Table 2. Cont.

Authors, Year Country Model Study Design Main Findings [Ref] Memantine incubation prevented the 4 experimental groups treated with either Dulbecco’s increase of inflammatory mediators (IL-6, modified Eagle’s medium), memantine (10 µM), 6-OHDA TNF-α) and oxidative predictors (100 µM), or 6-OHDA (100 µM) plus memantine (10 µM). (glutamate and LDH release), reversed the Quantification of PC12 cell death (via the CCK8 and the decrease in the total level of Nurr1, and apoptotic cells) and measurement of lactic dehydrogenase attenuated in a dose-dependent manner (LDH), glutamate, IL-6, and TNF-α; immunofluorescence for the increased level of Nur77, all induced by Wei et al., 2016 6-hydroxydopamine Nurr1, Nur77, Cyt c, and HSP60; and protein extraction for China 6-OHDA in PC12 cells. Memantine [26] (OHDA)-lesioned PC12 cells Nurr1, Nur77, hydroxylase (TH), dopamine decreased Cyt c and HSP60 release from transporter (DAT), brain-derived neurotrophic factor (BDNF), mitochondria of PC12 cells. phosphatidylinositol 3 kinase (PI3K)/p-PI3K, AKT/p-AKT, Cyt Memantine restored the reduced cell c, Lamin B1, and β-actin. Inhibition of the extracellular viability, attenuated the increased signal-regulated protein kinases (ERK), c-JunN-terminal apoptosis, and restored the reduction in the kinase (JNK) and p38 mitogen-activated protein kinases levels of TH and DAT in 6-OHDA-lesioned (MAPKs) PC12 cells Pre-treatment with memantine caused an important suppression of TNF-α-induced binding of THP-1 cells to HBMVEs in a Pre-treatment of HBMVEs with 10 or 20 µM memantine for 12 dose-dependent manner; rescued Primary human brain Wang et al., 2017 h (or 24 h) and incubation with 5 ng/mL TNF-α for another 12 TNF-α-induced disruption and interfered China microvascular endothelial [27] h (or 24 h). Measurement of adhesion of Human monocytic with THP-1 cells transmigration across a (HBMVE) cells cultures leukaemia cell line THP-1 cells. blood-brain BBB model, and prevented the increased expression of cell adhesion molecules (ICAM-1, VCAM-1, and E-selectin) induced by TNF-α. Four experimental groups for mice: controls, cigarette-smoking plus LPS, memantine, and cigarette-smoking plus LPS plus memantine. Determinations Memantine attenuated significantly the Chronic obstruction pulmonary in plasma, bronchoalveolar lavage fluid, and lung tissues. increase in the release of cytokines (TNF-α, Cheng et al., 2019 disease induced in mice by Two experimental groups for Raw265.7 for cells: IL-6, and IFN-γ) and glutamate, and the China [28] cigarette-smoking and LPS and cigarette-smoking exposure plus LPS, and cigarette-smoking increase of protein levels of NR-1 and xCT Raw264.7 cells cultures exposure plus LPS plus memantine. Measurement of Ca2+ and Ca2+ influx, and the activation of the influx, glutamate content, cytokines (TNF-α, IL-6, and IFN-γ) ERK1/2 pathway in the two models and proteins (p-ERK42/44, ERK1/2, p-AKT, NMDAR-1, xCT, GADPH) J. Pers. Med. 2020, 10, 217 11 of 15

Table 2. Cont.

Authors, Year Country Model Study Design Main Findings [Ref] Memantine (and not Ibuprofen) was able to prevent the increase in the expression of Experimental groups: controls, STZ, STZ plus ibuprofen (200 NMDAR1, NMDAR2B, Calpain, and µM), and STZ plus memantine (5 µM). Measurement of the Neuroinflammation and Caspase 3 expression, and the decrease in expression of NMDAR1, NMDAR2A, NMDAR2B, memory impairment induced the level of NMDAR2A, CaMKIIα, and Mishra et al., calcium/calmodulin-dependent protein kinase II subunit α India by intracerebroventricular CREB protein expression induced by STZ 2020 [29] (CaMKIIα), cyclic AMP-response element-binding (CREB) injection of streptozotocin (STZ) treatment. protein, Calpain, and Caspase 3; and levels of glial fibrillary in rats. Memantine and ibuprofen restored the acidic protein (GFAP), TNF-α, inducible nitric oxide synthase increase in the level of GFAP, TNF-α, and (iNOS), and IL-10. iNOS), and the decrease in the level of IL-10 induced by STZ treatment. J. Pers. Med. 2020, 10, 217 12 of 15

Author Contributions: F.J.J.-J.: Conceptualization, Methodology, Investigation, Validation, Formal analysis, Investigation, Writing—Original draft, Writing—review & editing, Project administration. H.A.-N.: Conceptualization, Methodology, Investigation, Validation, Formal analysis, Investigation, Writing—original draft, Writing—Review & editing, Project administration. E.G.-M.: Conceptualization, Methodology, Investigation, Validation, Formal analysis, Investigation, Writing—Original draft, Writing—Review & editing, Project administration, Obtaining funding. J.A.G.A.: Conceptualization, Methodology, Investigation, Validation, Formal analysis, Investigation, Writing—Original draft, Writing—Review & editing, Project administration, Obtaining funding. All authors have read and agreed to the published version of the manuscript. Funding: The work at the authors’ laboratory is supported in part by Grants PI15/00303, PI18/00540, and RETICS RD16/0006/0004 from Fondo de Investigación Sanitaria, Instituto de Salud Carlos III, Spain, and IB16170, GR18145 from Junta de Extremadura, Spain. Financed in part with FEDER funds from the European Union. Acknowledgments: We recognize the effort of the personnel of the Library of Hospital Universitario “Príncipe de Asturias”, Alcalá de Henares (Madrid, SPAIN), who retrieved an important number of papers for us. Conflicts of Interest: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Abbreviations

AD Alzheimer’s disease ALT alanine aminotransferase Arc activity-regulated cytoskeletal associated associated protein BBB blood-brain barrier BDNF brain derived neurotrophic factor CaMKIIα calcium/calmodulin-dependent protein kinase II subunit α CCK8 cholecystokinin8 CLP cecal ligation and puncture CREB protein cyclic AMP-response element-binding protein COVID-19 disease 2019 CSF Cerebrospinal fluid CTSL cathepsin L CytC Cytochrome C DAT Dopamine transporter EAE experimental allergic encephalomyelitis ERK1/2 extracellular signal-regulated kinase1/2 ETR. end-of-treatment response GDNF glial-derived neurotrophic factor 5-HT Serotonin 5-HT3 serotoninergic type 3 receptor HBMVE human brain microvascular endothelial HSPP60 heat shock protein 60 ICAM-1 intercellular adhesion molecule-1 IFNα2b interferon α2b IFNγ interferon γ IL-1β interleukin-1β IL-6 interleukin 6 iNOS Inducible nitric oxide synthase JNK c-Jun-NH2-terminal kinase LDH Lactic dehydrogenase LPS Lipopolysaccharide mGLUr metabotropic receptor MPP+ 1-methyl-phenyl-pyridinium ion mRNA messenger ribonucleic acid NF-κB nuclear factor-κB NMDA N-methyl-D-aspartate NMDAR1 or NR1 NMDA receptor 1 J. Pers. Med. 2020, 10, 217 13 of 15

Nurr77 reversing nerve growth factor IB 6-OHDA 6-hydroxydopamine PGE2 Prostaglandin E2 p38 MAP p38 mitogen-activated protein PD Parkinson’s disease PCR polymerase chain reaction PI3K phosphatidylinositol 3 kinase RANTES regulated on activation normal T cell expressed and secreted RT-PCR real-time polymerase chain reaction SARS-CoV severe acute respiratory syndrome SARS-CoV-2 coronavirus responsible for COVID-19 SCI Spinal cord injury STZ streptozotocin SVR sustained virological response TLRs toll-like receptors TNF-α tumour necrosis α VCAM-1 vascular cell adhesion molecule-1

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